PROJECT SUMMARY Adolescence is a vulnerable time period in which drug use can have lasting negative consequences into adulthood. However, the biology underlying this vulnerability, and how drugs modify the brain during adolescence, is unknown. Furthermore, it is unclear if males and females are equally vulnerable to drug use during adolescence, and if their vulnerability is due to the same molecular processes. One critical cell type that has been implicated in playing a role in this adolescent critical period is the resident immune cells of the brain, microglia. This project will explore the role of microglia in a brain region critically influenced by drugs of abuse, the nucleus accumbens (NAc), in male and female rats. To that end, I will first characterize what molecular processes to which microglia contribute that shape the development of the NAc during adolescence. Building upon this, I will next assess how adolescent drug use modifies function of microglia in these natural processes. Finally, I will determine the behavioral relevance of these observations by targeting microglia-dependent processes previously identified during adolescent NAc during drug use. Moreover, because all experiments will be performed in both male and female rats, this project is poised to determine if there is a sex-dependent regulation of molecular processes vulnerable to drug use. I expect this project to have several novel implications by bridging three bodies of research that are as yet considered disparate: (i) the molecular processes underlying vulnerability to addiction, (ii) neuroimmune responses to drugs of abuse, and (iii) the biology of relapse after long periods of abstinence.